Cerivastatin (Baycol), an HMG-CoA reductase inhibitor (statin), was removed from the market because of an increased risk of rhabdomyolysis. In the original application, we conducted a case-control study of rhabdomyolysis to evaluate 3 pharmacokinetic candidate genes as risk factors. A non-synonymous variant (V174A, SLCO1B1*5 allele) in the hepatic transporter increased the rhabdomyolysis risk, a finding that we validated in functional studies. The completed candidate-gene work in pharmacokinetics leaves largely unexplained the biologic mechanisms by which some patients develop rhabdomyolysis, the signature toxicity of statins. While basic-science work has identified candidate pathways such as protein prenylation and cytosolic-calcium release that are likely to contribute to rhabdomyolysis risk, the mechanism of toxicity remains undefined, and the available studies provide no evidence that cerivastatin influences risk by different mechanisms than other statins. The bimodal response--a serious drug reaction in a small proportion of users and none in the vast majority of users--suggests genetic factors as a potential cause. Indeed, our genome-wide association study (GWAS) provides evidence of additional undiscovered genetic loci that influence rhabdomyolysis risk. For some people, statins may be the equivalent of fluorinated- inhalation anesthetics, which precipitate malignant hyperthermia (MH) in susceptible individuals. We hypothesize that statin-induced rhabdomyolysis resembles a heterogeneous Mendelian disorder that may have several forms caused by genetic variants at many loci in multiple genes. Examples that result from gene-environment interactions include MH [many rare variants in 6 loci] and phenylketonuria [100s of variants in several genes]. General support for this hypothesis comes from our GWAS, which identified a genome-wide significant marker in the ryanodine receptor 2 gene, an intra-cellular calcium-release channel. The primary aim of this whole-exome-sequencing case-control study of rhabdomyolysis is to identify and characterize the genetic determinants and biologic mechanisms that underlie the pharmacodynamics of this toxic drug-response phenotype. Data and specimens from the rhabdomyolysis cases were collected during the original grant period, and controls come from the CHS and ARIC studies. The primary analysis will take place in a set of candidate genes (n~500). Whole-exome sequencing is an efficient method to screen a large number of genes for uncommon and disabling genetic variants. To address the issue of generalizability, collaboration with investigators conducting a large case-control study of rhabdomyolysis (n=250 cases) in the United Kingdom, primarily in users of simvastatin and atorvastatin, will provide opportunities for replication, meta-analysis, and improved power. For validation and translational work, co- investigators will use variants discovered by exome sequencing and replicated by our UK collaborators to conduct basic-science studies and evaluate their function. PUBLIC HEALTH RELEVANCE: The primary aim of this whole-exome-sequencing case-control study of rhabdomyolysis is to identify and characterize the genetic determinants and biologic mechanisms that underlie the pharmacodynamics of this toxic response to lipid-lowering statin drugs. The genes and the mechanisms identified in this study of rhabdomyolysis may also be important for the more mild and common forms of myopathy that are responsible for high rates of non-adherence with statin therapy. If genetic variants affect myopathy risk, screening for carriership may be appropriate for persons contemplating statins, especially as the use expands and the doses increase.